The present invention relates to processes for making pharmaceutical formulations or compositions containing an antifungal compound, in particular, the incorporation of an echinocandin/carbohydrate complex into an oral formulation or composition to enhance stability.
Oral formulations of pharmaceutical drugs may be administered to patients via sachets, chewable or conventional tablets, capsules or oral solutions and suspensions. The formulation that is developed for a particular drug is dependent on a variety of issues. For example, it is well-known in the art that an oral formulation should be sufficiently stable, have an acceptable appearance and be prepared from generally accepted, safe excipients.
Stability is an important consideration when designing a formulation, especially for oral applications. For practical and commercial reasons, it is desirable to maintain sufficient formulation stability for at least two years. Therefore, a primary formulation design goal is to optimize shelf-life and stability at the selected storage condition (e.g., room temperature).
The instability of the echinocandin compounds make them particularly difficult to formulate. Most of the formulations tested to date have a shelf life of less than one year at room temperature. Generally, a shelf life of at least two years is desirable. Therefore, there is a need for an oral formulation containing an echinocandin compound having improved thermal stability.
Applicants have discovered that the incorporation of one or more carbohydrates into an echinocandin formulation at specific process stages provides a significant improvement in thermal stability. In one embodiment of the present invention, a process is provided for preparing an oral pharmaceutical formulation which comprises (i) mixing an echinocandin compound or a echinocandin/carbohydrate complex and at least one carbohydrate in a solvent or mixture of solvents to form a pharmaceutical solution; (ii) spraying the solution onto a layer of fluidized granular diluent or carrier (e.g., a granular carbohydrate); and (iii) removing the excess solvent or solvents. The pharmaceutical solution may optionally contain surfactants, flavorings, colorants and/or processing aids. Oral granular pharmaceutical formulations prepared by the process described above are also provided, as well as medicaments prepared therefrom such as sachets and chewable tablets.
In another embodiment of the present invention, a process is provided for preparing an oral pharmaceutical formulation comprising the steps of: (i) mixing an echinocandin compound or echinocandin/carbohydrate complex, at least one carbohydrate, and a soluble granulating agent (e.g., polyvinylpyrrolidone) in a solvent or mixture of solvents to form a pharmaceutical solution; (ii) spraying the solution onto a layer of fluidized non-granular diluent or carrier (e.g., carbohydrate powders); and (iii) removing the excess solvent or solvents. The pharmaceutical solution may optionally contain surfactants, flavorings, colorants and/or processing aids. Oral granular pharmaceutical formulations prepared by the process described above are also provided, as well as medicaments prepared therefrom such as sachets and chewable tablets.
In yet another embodiment of the present invention, a method is provided for treating a fungal infection in a mammal in need thereof which comprises administering an oral formulation prepared by one of the processes described above to the mammal.
The term xe2x80x9cechinocandinxe2x80x9d refers to a compound having the following general structure: 
wherein:
R is an alkyl group, an alkenyl group, an alkynyl group, an aryl group, heteroaryl group, or combinations thereof;
R1, R2, R3, R6, R7, and R10 are independently hydroxy or hydrogen;
R4 is hydrogen, methyl or xe2x80x94CH2C(O)NH2;
R5 and R11 are independently methyl or hydrogen;
R8 is xe2x80x94OH, xe2x80x94OPO3H2, xe2x80x94OPO3HCH3, xe2x80x94OPO2HCH3, or xe2x80x94OSO3H; and
R9 is xe2x80x94H, xe2x80x94OH, or xe2x80x94OSO3H.
xe2x80x9cEchinocandin Bxe2x80x9d or xe2x80x9cECBxe2x80x9d refers to a echinocandin compound as described above where R1, R2, R3, R6, R7, R8, and R10 are hydroxy groups; R4, R5, and R11 are methyl groups; R9 is a hydrogen. In the natural product, R is a linoleoyl group. In a particularly useful semi-synthetic compound, R has both a rigid and a flexible component, for example, a compound where R is represented by the following formula 
The term xe2x80x9calkylxe2x80x9d refers to a hydrocarbon radical of the general formula CnH2n+1 containing from 1 to 30 carbon atoms unless otherwise indicated. The alkane radical may be straight, branched, cyclic, or multi-cyclic. The alkane radical may be substituted or unsubstituted. Similarly, the alkyl portion of an alkoxy group or alkanoate have the same definition as above.
The term xe2x80x9calkenylxe2x80x9d refers to an acyclic hydrocarbon containing at least one carbon-carbon double bond. The alkene radical may be straight, branched, cyclic, or multi-cyclic. The alkene radical may be substituted or unsubstituted.
The term xe2x80x9calkynylxe2x80x9d refers to an acyclic hydrocarbon containing at least one carbon carbon triple bond. The alkyne radical may be straight, or branched. The alkyne radical may be substituted or unsubstituted.
The term xe2x80x9carylxe2x80x9d refers to aromatic moieties having single (e.g., phenyl) or fused ring systems (e.g., naphthalene, anthracene, phenanthrene, etc.). The aryl groups may be substituted or unsubstituted. Substituted aryl groups include a chain of aromatic moieties (e.g., biphenyl, terphenyl, phenylnaphthalyl, etc.)
The term xe2x80x9cheteroarylxe2x80x9d refers to aromatic moieties containing at least one heteroatom within the aromatic ring system (e.g., pyrrole, pyridine, indole, thiophene, furan, benzofuran, imidazole, pyrimidine, purine, benzimidazole, quinoline, etc.). The aromatic moiety may consist of a single or fused ring system. The heteroaryl groups may be substituted or unsubstituted.
xe2x80x9cEchinocandin/carbohydrate complexxe2x80x9d refers to a crystalline complex formed between an echinocandin compound and a carbohydrate when the echinocandin is crystallized or recrystallized from a solvent in the presence of the carbohydrate. A more detailed description of the echinocandin/carbohydrate complexes may be found in Larew, et al., filed on Mar. 3, 1999 entitled xe2x80x9cEchinocandin/Carbohydrate Complexesxe2x80x9d and incorporated herein by reference.
xe2x80x9cCarbohydratexe2x80x9d refers to an aldehydic or ketonic derivative of polyhydric alcohols represented by the formulas Cn(H2O)n (e.g., glucose, C6(H2O)6; sucrose, C12(H2O)11). Carbohydrates include compounds with relatively small molecules, such as the simple sugars (e.g., monosaccharides, disaccharides, etc.), as well as macromolecular (polymeric) substances such as starch, glycogen, and cellulose polysaccharides. Sugars are carbohydrates (saccharides) having the general composition (CH2O)n and simple derivatives thereof. Although the simple monomeric sugars (glycoses) are described as polyhydroxy aldehydes or ketones, e.g., HOCH2xe2x80x94(CHOH)4xe2x80x94CHO for aldohexoses (e.g., glucose) or HOCH2xe2x80x94(CHOH)3xe2x80x94COCH2OH for 2-ketoses (e.g., fructose), the structures are commonly written as five (furanose) or six(pyranose) membered ring cyclic ethers, e.g. 
The term xe2x80x9cgranularxe2x80x9d diluents or carriers refer to materials where approximately 70% by weight of the material has a particle size greater than 150 microns.
The term xe2x80x9cnon-granularxe2x80x9d or xe2x80x9cpowderxe2x80x9d diluents or carriers refer to materials where approximately 70% by weight of the material has a particle size less than 150 microns.
The term xe2x80x9cgranulating agentxe2x80x9d refers to a binder that causes the diluent or carrier to bind together to form larger aggregates or granules upon spraying the agent onto the diluent powder surface in the presence of a solvent or solvents.